ObjectivesThe pathophysiology of bipolar disorder is likely to involve both genetic and environmental risk factors. In our study, we aimed to perform a systematic search of environmental risk factors for BD. In addition, we assessed possible hints of bias in this literature, and identified risk factors supported by high epidemiological credibility.
MethodsWe searched the Pubmed/MEDLINE, EMBASE and PsycInfo databases up to 7 October 2016 to identify systematic reviews and meta-analyses of observational studies that assessed associations between putative environmental risk factors and BD. For each meta-analysis, we estimated its summary effect size by means of both random- and fixed-effects models, 95% confidence intervals (CIs), the 95% prediction interval, and heterogeneity. Evidence of small-study effects and excess of significance bias was also assessed.
ResultsSixteen publications met the inclusion criteria (seven meta-analyses and nine qualitative systematic reviews). Fifty-one unique environmental risk factors for BD were evaluated. Six meta-analyses investigated associations with a risk factor for BD. Only irritable bowel syndrome (IBS) emerged as a risk factor for BD supported by convincing evidence (k=6; odds ratio [OR]=2.48; 95% CI=2.35-2.61; P

Exposure to the neurotropic parasite, Toxoplasma gondii, causes significant brain and behavioral anomalies in humans and other mammals. Understanding the cellular mechanisms of T. gondii-generated brain pathologies would aid the advancement of novel strategies to reduce disease. Complement factor C1 q is part of a classic immune pathway that functions peripherally to tag and remove infectious agents and cellular debris from circulation. In the developing and adult brain, C1 q modifies neuronal architecture through synapse marking and pruning. T. gondii exposure and complement activation have both been implicated in the development of complex brain disorders such as schizophrenia. Thus, it seems logical that mechanistically, the physiological pathways associated with these two factors are connected. We employed a rodent model of chronic infection to investigate the extent to which cyst presence in the brain triggers activation of cerebral C1 q. Compared to uninfected mice, cortical C1 q was highly expressed at both the RNA and protein levels in infected animals bearing a high cyst burden. In these mice, C1 q protein localized to cytoplasm, adjacent to GFAP-labeled astrocytes, near degenerating cysts, and in punctate patterns along processes. In summary, our results demonstrated an upregulation of cerebral C1q in response to latent T. gondii infection. Our data preliminarily suggest that this complement activity may aid in the clearance of this parasite from the CNS and in so doing, have consequences for the connectivity of neighboring cells and synapses.

Autoimmunity, gastrointestinal (GI) disorders and schizophrenia have been associated with one another for a long time. This paper reviews these connections and provides a context by which multiple risk factors for schizophrenia may be related. Epidemiological studies strongly link schizophrenia with autoimmune disorders including enteropathic celiac disease. Exposure to wheat gluten and bovine milk casein also contribute to non-celiac food sensitivities in susceptible individuals. Co-morbid GI inflammation accompanies humoral immunity to food antigens, occurs early during the course of schizophrenia and appears to be independent from antipsychotic-generated motility effects. This inflammation impacts endothelial barrier permeability and can precipitate translocation of gut bacteria into systemic circulation. Infection by the neurotropic gut pathogen, Toxoplasma gondii, will elicit an inflammatory GI environment. Such processes trigger innate immunity, including activation of complement C1q, which also functions at synapses in the brain. The emerging field of microbiome research lies at the center of these interactions with evidence that the abundance and diversity of resident gut microbiota contribute to digestion, inflammation, gut permeability and behavior. Dietary modifications of core bacterial compositions may explain inefficient gluten digestion and how immigrant status in certain situations is a risk factor for schizophrenia. Gut microbiome research in schizophrenia is in its infancy, but data in related fields suggest disease-associated altered phylogenetic compositions. In summary, this review surveys associative and experimental data linking autoimmunity, GI activity and schizophrenia, and proposes that understanding of disrupted biological pathways outside of the brain can lend valuable information regarding pathogeneses of complex, polygenic brain disorders. (C) 2014 Elsevier B.V. All rights reserved.

OBJECTIVES
:
Toxoplasma gondii
, the protozoan parasite infecting about 30%
population worldwide, is suspected to be the etiological agent of certain form
of schizophrenia disease.
To x o p l a s m a
is known to change levels of certain neu-
rotransmitters, cytokines and several hormones in both infected animals and
humans. A common feature of toxoplasmosis and schizophrenia is a disorder of
immune system.
METHODS:
Here we studied the levels of five neuro- and immunomodulatory
steroids, selected hormones and lipids in sera of 173 schizophrenia patients.
RESULTS:
To x o p l a s m a
infected schizophrenia patients expressed only insignifi-
cantly lower concentration of neuro- and immunomodulatory DHEA metabo-
lites. Infected women had higher concentration of glucose while infected men had
higher concentration of cholesterol and LDL cholesterol. No significant effect of
human cytomegalovirus infection on the concentration of the above parameters
was observed. The difference in the concentration of DHEA metabolites faded
with the decrease of the concentration of anti-
To x o p l a s m a
IgG antibodies (i.e.
with the duration of
To x o p l a s m a
infection) while the difference in the concentra-
tion of cholesterol and LDL-cholesterol increased with the decrease of the con-
centration of anti-
To x o p l a s m a
IgG antibodies. The prevalence of toxoplasmosis in
male (53.2%) but not female (29.8%) schizophrenia
patients was unusually high in
comparison with prevalence of toxoplasmosis in a general population.
CONCLUSION:
Our results provided an explanation for seemingly decreasing
prevalence of toxoplasmosis in schizophrenia patients observed in current studies (increased concerns about the rights of patients result-
ing in absence of non-cooperative
To x o p l a s m a
-positive
patients in the study population) and suggest possible
explanation for reported positive correlation between
prevalence of toxoplasmosis and incidence of cardio-
vascular diseases (accelerated atherosclerotic develop-
ment due to increased level of cholesterol and LDL in
To x o p l a s m a
infected humans).

Bipolar disorder is now known to be associated not only with highly prevalent co-occurring psychiatric and substance use disorders but also with medical comorbidities, such as cardiovascular diseases, diabetes mellitus, obesity and thyroid dysfunction. Inflammatory disturbances repeatedly observed in bipolar disorder, can explain some of the comorbidity between bipolar disorder and medical disorder. This revised perspective of bipolar disorders should promote the development of therapeutic tools. Immuno-inflammatory dysfunction may well represent a significant component of the underlying pathophysiology of the disorder. We therefore propose to review the immuno-inflammatory hypothesis in bipolar disorder considering the co-occurence with autoimmune diseases, immunological and inflammatory markers, as well as immuno-genetic markers which could lead to personalized treatments.

nfections have been suggested to play a role in the etiology of schizophrenia, but the evidence for this has been inconsistent. Schizophrenia patients have an increased risk of infections as a result of hospitalizations or life style factors. Therefore a study on early subclinical manifestations of psychosis in relation to virus infections is warranted. We examined whether serum antibodies against human Herpes viruses and Toxoplasma gondii were associated with subclinical symptoms of psychosis in adolescents.
Data were collected as part of the TRacking Adolescents' Individual Lives Survey (TRAILS) cohort, a large prospective cohort of Dutch adolescents. A total of 1176 participants with an available Community Assessment of Psychic Experiences (CAPE) and an available blood sample were included in this analysis. Solid-enzyme immunoassay methods were used to measure the presence of immunoglobulin G (IgG) antibodies in serum to the Herpes virus family and to T. gondii.
There was no significant association between serologic evidence of infection with human Herpes viruses or T. gondii and the risk of subclinical positive experience of psychosis. Subjects with a positive serological reaction to Epstein-Barr Virus (EBV) had higher scores on the positive dimension of psychosis measured by CAPE (b = 0.03, P = 0.02). This significant association was observed in males, but not in females.
The current study suggests that there is no significant association between serological evidence of infection to human Herpes viruses and positive subclinical experience of psychosis, whereas there was an association between EBV infection and subclinical psychotic symptoms in boys.